Diabetes damages the retina, and the resulting diabetic retinopathy (DR) is the leading cause of visual impairment and blindness in working-aged adults. Despite this, the pathogenesis of DR is poorly understood. Research done by us and others strongly implicates inflammatory processes in the development of the critical microvascular lesions of DR, and work done during our current Merit research demonstrates that the induction of these inflammatory proteins by hyperglycemia is regulated by protein acetylation. The central hypothesis of our current proposal is that increased acetylation of proteins in diabetes contribute to the degeneration of retinal capillaries via inflammatory pathways, and that leukocytes in particular play a critical role in the pathogenesis of this acetylation-driven degeneration of retinal capillaries. Using 2 models of DR (streptozotocin to induce a Type 1 diabetes, and spontaneously diabetic db/db mice which are a model of Type 2 diabetes), research in this proposal will determine if inhibition of this acetylatin systemically (Aim 1) or in leukocytes only (Aim 2) inhibits development of the characteristic vascular lesions of early DR. These studies will be performed both as prevention trials and as intervention trials. The third aim of this proposal will extend these studies to patients, using leukocytes from Veterans (both diabetic and nondiabetic) to determine if leukocyte- mediated killing of retinal endothelial cells in diabetes can be prevented by inhibiting or reversing acetylation of proteins in leukocytes. We also will begin to explore if the extent of acetylation-mediated killing of retinal endothelial cells by leukocytes from diabetic patients correlates with the severity of retinopathy and might predict which patients are most susceptible to develop advanced DR.